Benzofuran Derivatives Research Articles

Discovery of Some Heterocyclic Molecules as Bone Morphogenetic Protein 2 (BMP-2)-Inducible Kinase Inhibitors: Virtual Screening, ADME Properties, and Molecular Docking Simulations.

Bone morphogenetic proteins (BMPs) are growth factors that have a vital role in the production of bone, cartilage, ligaments, and tendons. Tumors’ upregulation of bone morphogenetic proteins (BMPs) and their receptors are key features of cancer progression. Regulation of the BMP kinase system is a new promising strategy for the development of anti-cancer drugs. In this work, based on a careful literature study, a library of benzothiophene and benzofuran derivatives was subjected to different computational techniques to study the effect of chemical structure changes on the ability of these two scaffolds to target BMP-2 inducible kinase, and to reach promising candidates with proposed activity against BMP-2 inducible kinase. The results of screening against Lipinski’s and Veber’s Rules produced twenty-one outside eighty-four compounds having drug-like molecular nature. Computational ADMET studies favored ten compounds (11, 26, 27, 29, 30, 31, 34, 35, 65, and 72) with good pharmacokinetic profile. Computational toxicity studies excluded compound 34 to elect nine compounds for molecular docking studies which displayed eight compounds (26, 27, 29, 30, 31, 35, 65, and 72) as promising BMP-2 inducible kinase inhibitors. The nine fascinating compounds will be subjected to extensive screening against serine/threonine kinases to explore their potential against these critical proteins. These promising candidates based on benzothiophene and benzofuran scaffolds deserve further clinical investigation as BMP-2 kinase inhibitors for the treatment of cancer.

Friedel-Crafts alkylation oxidative cyclization catalyzed by co-oxidation of SeO2 and FeCl3: a simple synthesis of benzo[b]furan from acetophenone and anisole

A simple one-pot method was developed to complete the α-diphenyl substitution and cyclization of acetophenone using acetophenone and substituted benzene as substrates, and a series of benzofuran derivatives was synthesized efficiently. It had the advantages of medium to excellent yield and easily obtained substrate. Compared with other methods, the method avoids the use of precious metals and cumbersome operations.

Synthesis and Biological Evaluation of Novel 2-(Benzofuran-2-yl)-chromone Derivatives for In Vivo Imaging of Prion Deposits in the Brain.

Prion diseases are fatal neurodegenerative disorders caused by the deposition of scrapie prion protein aggregates (PrPSc) in the brain. We previously reported that styrylchromone (SC) and benzofuran (BF) derivatives have potential as imaging probes for PrPSc. To further improve their properties, we designed and synthesized 2-(benzofuran-2-yl)-chromone (BFC) derivatives hybridized with SC and BF backbones as novel single-photon emission computed tomography probes for the detection of cerebral PrPSc deposits. Recombinant mouse prion protein (rMoPrP) aggregates and mouse-adapted bovine spongiform encephalopathy (mBSE)-infected mice were used to evaluate the binding properties of BFC derivatives to PrPSc. The BFC derivatives exhibited high binding affinities (equilibrium dissociation constant [Kd] = 22.6-47.7 nM) for rMoPrP aggregates. All BFC derivatives showed remarkable selectivity against amyloid beta aggregates. Fluorescence microscopy confirmed that the fluorescence signals of the BFC derivatives corresponded to the antibody-positive deposits of PrPSc in mBSE-infected mouse brains. Among the BFC derivatives, [125I]BFC-OMe and [125I]BFC-NH2 exhibited high brain uptake and favorable washout from the mouse brain. In vitro autoradiography demonstrated that the distribution of [125I]BFC-OMe in the brain tissues of mBSE-infected mice was colocalized with PrPSc deposits. Taken together, BFC derivatives appear to be promising prion imaging probes.

PPh3-Triggered Tandem Synthesis of 2,3-Disubstituted Benzofuran Derivatives from o-Quinone Methides with Acyl Chlorides

A PPh3-triggered tandem strategy for the efficient synthesis of valuable 2,3-disubstituted benzofuran derivatives in generally good to high yields from aryl or alkyl acyl chlorides and o-quinone methides has been developed. This method features mild reaction conditions, simple operation, and a broad substrate scope.

Advances in Synthetic Strategies and Medicinal Importance of Benzofurans: A Review

AbstractOut of the many heterocycles that exhibit pharmaceutical and therapeutic properties, benzofurans remain the most eye‐catching to scientists ever since their discovery. From being present in natural products to synthetic analogs they show diverse biological properties which are used to treat various diseases. Interestingly, some of the benzofuran hybrids were docked against COVID‐19 Main Protease and it showed appealing results. Apart from medicinal properties it also exhibits some non‐drug applications. The structure activity relationship of benzofuran derivatives in many infections draws attention to the extent where drugs can be produced in a short time span which highlights their significance in medicinal chemistry. There are considerable reaction schemes to synthesize this moiety either simple one pot reactions or multistep. Here, we emphasize on the chemistry of benzofurans, synthesis and its derivatives in the recent years, some of which show notable anti‐tumor, anti‐fungal, anti‐mycobacterial and anti‐oxidant activities.

124I]IBETA: A New Aβ Plaque Positron Emission Tomography Imaging Agent for Alzheimer's Disease.

Several fluorine-18-labeled PET β-amyloid (Aβ) plaque radiotracers for Alzheimer’s disease (AD) are in clinical use. However, no radioiodinated imaging agent for Aβ plaques has been successfully moved forward for either single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. Radioiodinated pyridyl benzofuran derivatives for the SPECT imaging of Aβ plaques using iodine-123 and iodine-125 are being pursued. In this study, we assess the iodine-124 radioiodinated pyridyl benzofuran derivative 5-(5-[124I]iodobenzofuran-2-yl)-N,N-dimethylpyridin-2-amine ([124I]IBETA) (Ki = 2.36 nM) for utilization in PET imaging for Aβ plaques. We report our findings on the radioiododestannylation reaction used to prepare [124/125I]IBETA and evaluate its binding to Aβ plaques in a 5 × FAD mouse model and postmortem human AD brain. Both [125I]IBETA and [124I]IBETA are produced in >25% radiochemical yield and >85% radiochemical purity. The in vitro binding of [125I]IBETA and [124I]IBETA in transgenic 5 × FAD mouse model for Aβ plaques was high in the frontal cortex, anterior cingulate, thalamus, and hippocampus, which are regions of high Aβ accumulation, with very little binding in the cerebellum (ratio of brain regions to cerebellum was >5). The in vitro binding of [125I]IBETA and [124I]IBETA in postmortem human AD brains was higher in gray matter containing Aβ plaques compared to white matter (ratio of gray to white matter was >5). Anti-Aβ immunostaining strongly correlated with [124/125I]IBETA regional binding in both the 5 × FAD mouse and postmortem AD human brains. The binding of [124/125I]IBETA in 5 × FAD mouse and postmortem human AD brains was displaced by the known Aβ plaque imaging agent, Flotaza. Preliminary PET/CT studies of [124I]IBETA in the 5 × FAD mouse model suggested [124I]IBETA was relatively stable in vivo with a greater localization of [124I]IBETA in the brain regions with a high concentration of Aβ plaques. Some deiodination was observed at later time points. Therefore, [124I]IBETA may potentially be a useful PET radioligand for Aβ plaques in brain studies.

Design, synthesis and biological evaluation of novel aminopropylcarboxamide derivatives as sigma ligands

In our continuing effort to develop novel sigma receptor (SR) ligands, we present the design, synthesis and binding studies of a small library of aminopropylcarboxamide derivatives, obtained from a deconstruction of the piperidine ring of previously synthesized piperidine-based compounds. The best results were achieved with benzofuran (5c, 5g) and quinoline (5a, 5e) derivatives. These compounds revealed the highest affinity for both receptor subtypes. In particular, the 3,4-dimethoxyphenyl derivatives 5e and 5g showed the highest selectivity profile for S2R, especially the quinoline derivative 5e exhibited a 35-fold higher affinity for S2R subtype. The cytotoxic activity of aforementioned compounds was evaluated against SKBR3 and MCF7 cell lines, widely used for breast cancer studies. Whereas the potency of 5g was similar that of Siramesine and Haloperidol in both cell lines, compounds 5a, 5c and 5e exhibited a potency at least comparable to that of Haloperidol in SKBR3 cells. A molecular modelling evaluation towards the S2R binding site, confirmed the strong interaction of compound 5e thus justifying its highest S2R affinity.

Structure-Activity Relationship of Benzofuran Derivatives with Potential Anticancer Activity.

Simple SummaryCancer is the leading cause of death worldwide and responsible for killing approximately 10 million people per year. Fused heterocyclic ring systems such as benzofuran have emerged as important scaffolds with many biological properties. Furthermore, derivatives of benzofurans demonstrate a wide range of biological and pharmacological activities, including anticancer properties. The main aim of this review is to highlight and discuss the contribution of benzofuran derivatives as anticancer agents by considering and discussing the chemical structure of 20 different compounds. Evaluating the chemical structure of these compounds will guide future medicinal chemists in designing new drugs for cancer therapy that might give excellent results in in vivo/in vitro applications.Benzofuran is a heterocyclic compound found naturally in plants and it can also be obtained through synthetic reactions. Multiple physicochemical characteristics and versatile features distinguish benzofuran, and its chemical structure is composed of fused benzene and furan rings. Benzofuran derivatives are essential compounds that hold vital biological activities to design novel therapies with enhanced efficacy compared to conventional treatments. Therefore, medicinal chemists used its core to synthesize new derivatives that can be applied to a variety of disorders. Benzofuran exhibited potential effectiveness in chronic diseases such as hypertension, neurodegenerative and oxidative conditions, and dyslipidemia. In acute infections, benzofuran revealed anti-infective properties against microorganisms like viruses, bacteria, and parasites. In recent years, the complex nature and the number of acquired or resistant cancer cases have been largely increasing. Benzofuran derivatives revealed potential anticancer activity with lower incidence or severity of adverse events normally encountered during chemotherapeutic treatments. This review discusses the structure–activity relationship (SAR) of several benzofuran derivatives in order to elucidate the possible substitution alternatives and structural requirements for a highly potent and selective anticancer activity.

Identification of 3-(piperazinylmethyl)benzofuran derivatives as novel type II CDK2 inhibitors: design, synthesis, biological evaluation, and in silico insights

In the current work, a hybridisation strategy was adopted between the privileged building blocks, benzofuran and piperazine, with the aim of designing novel CDK2 type II inhibitors. The hybrid structures were linked to different aromatic semicarbazide, thiosemicarbazide, or acylhydrazone tails to anchor the designed inhibitors onto the CDK2 kinase domain. The designed compounds showed promising CDK2 inhibitory activity. Compounds 9h, 11d, 11e and 13c showed potent inhibitory activity (IC50 of 40.91, 41.70, 46.88, and 52.63 nM, respectively) compared to staurosporine (IC50 of 56.76 nM). Moreover, benzofurans 9e, 9h, 11d, and 13b showed promising antiproliferative activities towards different cancer cell lines, and non-significant cytotoxicity on normal lung fibroblasts MRC-5 cell line. Furthermore, a cell cycle analysis as well as Annexin V-FITC apoptosis assay on Panc-1 cell line were performed. Molecular docking simulations were performed to explore the ability of target benzofurans to adopt the common binding pattern of CDK2 type II inhibitors.

N-heterocyclic carbene-stabilized metal nanoparticles within porous organic cages for catalytic application.

Tuning the surface-embellishing ligands of metal nanoparticles (NPs) is a powerful strategy to modulate their morphology and surface electronic and functional features, impacting their catalytic activity and selectivity. In this work, we report the design and synthesis of a polytriazolium organic cage PIC-T, capable of stabilizing PdNPs within its discrete cavity. The obtained material (denoted Pd@PCC-T) is highly durable and monodispersed with narrow particle-size distribution of 2.06 ± 0.02 nm, exhibiting excellent catalytic performance and recyclability in the Sonogashira coupling and tandem reaction to synthesize benzofuran derivatives. Further investigation indicates that the modulation of N-heterocyclic carbene sites embedded in the organic cage has an impact on NPs’ catalytic efficiency, thus providing a novel methodology to design superior NP catalysts.

Identification of potent inhibitors against chorismate synthase of Toxoplasma gondii using molecular dynamics simulations

Toxoplasmosis, caused by Toxoplasma gondii, affects about 20–30% of the human population every year globally. The emergence of severe side effects of current chemotherapeutics and drug-resistant strains emphasize upon finding new therapeutics to treat toxoplasmosis. Chorismate synthase (CS) is a vital enzyme of shikimate pathway and responsible for formation of chorismate, which acts as a precursor for production of several aromatic compounds important for virulence and survival in many bacteria and protozoans. In this study, comparative modeling was employed to predict the three-dimensional structure of T. gondii chorismate synthase (TgCS) followed by its refinement and validation using various computational tools. The modeled structure of TgCS monomer shows all the conserved features of CS, particularly the beta-alpha-beta sandwich fold. Molecular docking studies has displayed that 5-enolpyruvylshikimate-3-phosphate (EPSP, substrate) and flavin mononucleotide (FMN, cofactor) bind into the active site of TgCS and all the structures (apo, binary, and ternary) were observed to be stable during molecular dynamics (MD) simulation. Subsequently, structure-based virtual screening using TgCS has inferred two of each benzofuran and EPSP analogs as the best hits on the basis of RCS, molecular interactions, ADME properties, and MD simulations. The MD data of resultant protein–ligand complex structures was subjected to calculate the binding energy through MMPBSA method, which highlights that the EPSP analogs have higher binding affinity for the substrate-binding site of TgCS in comparison to benzofuran derivatives as well as substrate. Altogether, our study could pave the way for designing and development of next generation chemotherapeutic molecules against toxoplasmosis.

A new library of 1,2,3‐triazole based benzofuran scaffolds: Synthesis and biological evaluation as potential antimicrobial agents

AbstractA library of new 1,2,3‐triazole based benzofuran derivatives was constructed via synthesizing them through the Rap‐Stoermer reaction in moderate to good yields. Various reaction conditions were examined to develop an optimized synthetic route for affording the desired products in good yields. All the synthesized compounds were characterized by 1H‐NMR, 13C‐NMR, FT‐IR, and mass spectral data. The title compounds were screened in vitro for their potential antimicrobial properties and most of the compounds exhibited promising antimicrobial activities.

Antitumor and multikinase inhibition activities of some synthesized coumarin and benzofuran derivatives.

Two new series of coumarin and benzofuran derivatives were designed, synthesized, and assessed for their in vitro and in vivo antitumor activities against breast cancer. Compounds 8, 9, 14, 15, and 17 exhibited the best antiproliferative activities (IC50 : 0.07-2.94 μM) against the MCF-7 cell line, compared with lapatinib (IC50 : 4.69 μM). Compound 14, with the most potent cytotoxic activity against MCF-7 cells, was capable of enhancing preG1 apoptosis and triggering cell cycle arrest at the G2/M phase. The kinase inhibitory activity of compound 14 against a panel of 22 kinases was examined to reveal multikinase inhibition within -39% to -97%. Furthermore, compound 14 exhibited potent in vivo Ehrlich (mammary adenocarcinoma) tumor regression, positive caspase-3, and negative EGFR immunoreaction, and was capable of elevating the catalase level. The physicochemical properties and pharmacokinetic parameters of compound 14 were investigated in silico for its druglikeness.

Structural Insight of New Butyrylcholinesterase Inhibitors Based on Benzylbenzofuran Scaffold.

In the present work, we use a merger of computational and biochemical techniques as a rational guideline for structural modification of benzofuran derivatives to find pertinent structural features for the butyrylcholinesterase inhibitory activity and selectivity. Previously, we revealed a series of 2-phenylbenzofuran compounds that displayed a selective inhibitory activity for BChE. Here, in an effort to discover novel selective BChE inhibitors with favorable physicochemical and pharmacokinetic profiles, 2-benzylbenzofurans were designed, synthesized, and evaluated as BChE inhibitors. The 2-phenylbenzofuran scaffold structure is modified by introducing one methylene spacer between the benzofuran core and the 2-phenyl ring with a hydroxyl substituent in the para or meta position. Either position 5 or 7 of the benzofuran scaffold was substituted with a bromine or chlorine atom. Further assessment of the selected list of compounds indicated that the substituent’s nature and position determined their activity and selectivity. 5-bromo-2-(4-hydroxybenzyl)benzofuran 9B proved to be the most potent butyrylcholinesterase inhibitor (IC50 = 2.93 µM) of the studied series. Computational studies were carried out to correlate the theoretical and experimental binding affinity of the compounds to the BChE protein.

Palladium-Catalyzed Cascade 5-endo-dig Cyclization of Ynamides to Form 4-Alkynyloxazolones.

The selective synthesis of 4-alkynyloxazolones and their further applications as substrates to electrophile-promoted nucleophilic cyclization have been developed. The reaction of ynamides with terminal alkynes proceeded smoothly to give 4-alkynyloxazolones in the presence of a catalytic amount of palladium(II) acetate. The products were obtained with the sequential formation of new C-C and C-O bonds via a cascade procedure. The first step involved a carbon-oxygen bond formation, via a 5-endo-dig closure, which was confirmed by X-ray analyses of the crystalline sample. Subsequently, the reaction of 4-alkynyloxazolones with an electrophilic selenium source gave 3-phenylselanyl benzofuran derivatives via an electrophile-promoted nucleophilic cyclization.

Protein Binding of Benzofuran Derivatives: A CD Spectroscopic and In Silico Comparative Study of the Effects of 4-Nitrophenyl Functionalized Benzofurans and Benzodifurans on BSA Protein Structure.

Benzofuran derivatives are synthetic compounds that are finding an increasing interest in the scientific community not only as building blocks for the realization of new materials, but also as potential drugs thanks to their ability to interact with nucleic acids, interfere with the amyloid peptide aggregation and cancer cell cycle. However, their ability to interact with proteins is a theme still in need of investigation for the therapeutic importance that benzofurans could have in the modulation of protein-driven processes and for the possibility of making use of serum albumins as benzofurans delivery systems. To this scope, we investigated the protein binding ability of two 4-nitrophenyl-functionalized benzofurans previously synthesized in our laboratory and herein indicated as BF1 and BDF1, which differed for the number of furan rings (a single moiety in BF1, two in BDF1), using bovine serum albumin (BSA) as a model protein. By circular dichroism (CD) spectroscopy we demonstrated the ability of the two heteroaromatic compounds to alter the secondary structure of the serum albumin leading to different consequences in terms of BSA thermal stability with respect to the unbound protein (ΔTm > 3 °C for BF1, −0.8 °C for BDF1 with respect to unbound BSA, in PBS buffer, pH 7.5) as revealed in our CD melting studies. Moreover, a molecular docking study allowed us to compare the possible ligand binding modes of the mono and difuranic derivatives showing that while BF1 is preferentially housed in the interior of protein structure, BDF1 is predicted to bind the albumin surface with a lower affinity than BF1. Interestingly, the different affinity for the protein target predicted computationally was confirmed also experimentally by fluorescence spectroscopy (kD = 142.4 ± 64.6 nM for BDF1 vs. 28.4 ± 10.1 nM for BF1). Overall, the above findings suggest the ability of benzofurans to bind serum albumins that could act as their carriers in drug delivery applications.

Development of novel 67/68Ga-labeled pyridyl benzofuran derivatives as islet amyloid imaging probes

IntroductionType 2 diabetes mellitus (T2DM) accounts for the majority of diabetes mellitus cases, and β-cell function and mass may be involved in its pathophysiology. The deposition of islet amyloid in pancreas islets is one of the mechanisms of progression of T2DM. Therefore, the development of imaging techniques for islet amyloid deposition contributes to the early-phase diagnosis and elucidation of the pathogenic mechanism of T2DM. We have reported that pyridyl benzofuran (PBF) is a promising scaffold for islet amyloid imaging probes. In this study, we designed [67/68Ga]Ga-dedpa-(PBF)2, which contains two PBF scaffolds in one molecule for enhancing binding affinity for islet amyloid by multivalent interaction, and evaluated its utility as an islet amyloid imaging probe. MethodsWe synthesized dedpa-PBF and dedpa-(PBF)2 as mono and bivalent compounds, respectively. We conducted an in vitro saturation binding assay for calculation of the dissociation constants (Kd) against islet amyloid aggregates. An in vitro autoradiographic study was performed using pancreatic tissue sections of T2DM patients. A biodistribution experiment was performed using normal mice. Finally, we carried out an ex vivo autoradiographic study using islet amyloid-transplanted model mice. ResultsIn the in vitro saturation binding assay, the affinity of [67Ga]Ga-dedpa-(PBF)2 (Kd = 2.46 ± 0.49 μM) for islet amyloid aggregates was higher than that of [67Ga]Ga-dedpa-PBF (Kd = 3.73 ± 1.75 μM). The in vitro autoradiographic study revealed that both compounds clearly labeled islet amyloid depositions in T2DM sections. In the biodistribution experiment using normal mice, both compounds had initial uptake in the pancreas, but retention of radioactivity was observed in the pancreas and surrounding organs. In ex vivo autoradiography, both compounds exhibited intensive accumulation of radioactivity, which corresponded to Thioflavin S staining in amylin-transplanted mouse pancreas. Conclusion[67/68Ga]Ga-dedpa-(PBF)2 demonstrated the fundamental characteristics of an islet amyloid imaging probe, although it is necessary to improve the clearance from organs.

Dearomatization/Deiodination of o-Iodophenolic Compounds with α,β-Unsaturated Imines for Accessing Benzofuran Derivatives

A dearomatization/deiodination/rearomatization strategy for the [3 + 2] cyclization of o-iodophenolic substrates with α,β-unsaturated imines to construct various dihydrobenzofuran-related skeletons has been established. Tolerance to different functional groups has been tested. Mechanistic studies revealed that this domino reaction was possibly realized by the deiodination and tautomerization of the key dearomatized intermediate to generate a free phenolic O radical. Moreover, an anticancer agent 4 and an α-glucosidase inhibitor 5 with high bioactivities were successfully synthesized using this novel protocol.

Interaction of arylbenzoquinones with enamines. Synthesis of 4-aryl-5a-morpholin-4-yl-5a,6,7,8,9,9a-hexahydro-dibenzo[b,d]furan-2-oles

An important way of forming the indole cycle is the Nenitsescu reaction. Convenient precursors for this reaction are readily available β-ketoesters or 1,3-diketones, which after conversion to enamines react with 1,4-quinones to form polysubstituted indoles. The regio- and chemoselectivity of the interaction depends on the conduction conditions, the structure of the quinone and enamine component, and the electronic effects of the substituents. Studies have shown that the condensation of quinones with enamines can take place in at least a few main directions. The most common are 5- or 6-hydroxyindoles, 5-hydroxybenzofurans and 5-hydroxyindazoles. However, the synthetic potential of the reaction is not limited to this, because it also allows to obtain other, more diverse structures that are difficult to access in other ways – benzocarbazoles, pyrido- [2,3- b ]indoles, furo[3,2- h ]indoles, furo[2,3- g ]indoles, imidazo[4,5- g ]indoles, dihydro-benzo[ g ]indoles, pyrrolo[2,3- h ]quinolines. However, interest in this reaction has not diminished to this day, as it is a convenient method of forming a base fragment for many biologically active substances. In this paper, we describe the results of studies obtained during the study of the reactivity of monoarylquinones to enamines derived from cyclic ketones and secondary amines. With the use of such enamines, it is impossible to obtain indoles by the Nenitsescu reaction, so the formation of benzofuran derivatives was expected, but the question of regioselectivity of the process remained open. It was found that the interaction of 1-morpholino-1-cyclohexene 6 with 2-aryl-1,4-benzoquinones 1 – 5 at room temperature in a dry benzene forms 4-aryl-5a-morpholin-4-yl-5a,6,7,8,9,9a-hexahydrodibenzo[ b , d ]furan-2-oles 7 – 11 . The reaction was found to be regioselective – of the three possible regioisomers, only 4-aryl-substituted dibenzofurans were formed, and no indole cyclization products were detected. The structures of the synthesized compounds were confirmed by the 1 H-, 13 C NMR spectroscopy and element analysis data. Keywords: 2-aryl-1,4-benzoquinones, 1-morpholino-1-cyclohexen, enamines, Nenitzescu reaction, dibenzo[ b , d ]furan-2-ones, heterocycles.

Dual-state emissionversusno emission by manipulating the molecular structures of cyanovinyl–benzofuran derivatives

A very small change in the molecular structure of D–A cyanostilbene derivatives enables non-emissive derivatives to become ones presenting high luminescence both in solution and in the solid state.